This application is a Rule 371 Application of PCT Application No. EP99/09320, filed Dec. 1, 1999, which claims priority to GB Application Serial No. 9826412.0, filed Dec. 3, 1998.
This invention relates to novel compounds which inhibit hepatic production of apoprotein B-100 (apoB-100), and to processes for their preparation, pharmaceutical compositions containing them and their medical use.
ApoB-100 is the main protein component of low density lipoprotein-cholesterol (LDL-C). High LDL-C plasmatic levels are a major risk factor for atherosclerosis and coronary, artery diseases. ApoB-100 plasmatic levels correlate with LDL-C plasmatic levels and also constitute a cardiovascular risk factor in themselves. ApoB-100 is exclusively produced by hepatocytes and reducing hepatic production of ApoB-100 should induce a decrease of LDL-C plasmatic levels.
Compounds having ApoB-100 inhibition properties have been described in WO96/40640, which is incorporated herein by reference.
The present invention provides a compound of formula (I) 
wherein
A represents N or CH;
X is selected from the following groups:
(i) xe2x80x94C1-6alkylene-, optionally containing one or two double bonds and optionally substituted by one or more hydroxy, C1-6alkyl, C1-6alkoxy, C1-6acyl or C1-6acyloxy groups,
(ii) oxo, sulfonyl, thioxo,
(iii) xe2x80x94C1-6alkylenecarbonyl-,xe2x80x94C1-6alkylenesulfonyl-,xe2x80x94C1-6alkylenethioxo-,
(iv) xe2x80x94C2-6alkyleneoxy-, xe2x80x94C2-6alkylenethio-, xe2x80x94C2-6alkylene(Nxe2x80x94H or Nxe2x80x94C1-6alkyl)amino-,
(v) xe2x80x94C1-6alkylenecarboxy-, xe2x80x94C1-6alkylenethioamido-, xe2x80x94C1-6alkylene(Nxe2x80x94H or Nxe2x80x94C1-6alkyl)carboxamido-, and
(vi) xe2x80x94C2-6alkyleneoxycarbonyl-, xe2x80x94C2-6alkylenethiocarbonyl-, xe2x80x94C2-6alkylene(Nxe2x80x94H or Nxe2x80x94C1-6alkyl)aminocarbonyl-;
Z represents a direct link or xe2x80x94C1-6alkylene-, optionally containing one double bond and optionally substituted by one or more hydroxy, C1-6alkyl, C1-6alkoxy, C1-6acyl or C1-6acyloxy groups;
R1 is selected from the following groups:
(i) hydrogen, C1-3perfluoroalkyl,
(ii) C6-10 aryl, C3-8cycloalkyl and fused benz derivatives thereof, C7-10polycycloalkyl, C4-8cycloalkenyl, C7-10polycycloalkenyl,
(iii) a heterocyclyl selected from the group consisting of monocyclic radicals and fused polycyclic radicals, wherein said, radicals contain a total of from 5-14 ring atoms, wherein said radicals contain a total of from 1-4 ring heteroatoms independently selected from oxygen, nitrogen and sulfur, and wherein individual rings of said radicals may be independently saturated, partially unsaturated, or aromatic, and
(iv) where either X is C1-6alkylene and Z is a direct link, or Z is C1-6alkylene, R1 additionally may represent a halogen, cyano, nitro or C1-6acyl group,
xe2x80x83wherein, when R1 contains one or more rings, said rings may each independently bear 0 to 4 substituents independently selected from
(i) halogen, hydroxy, cyano, nitro, formyl, C1-6alkylsulfonylamino,
(ii) C1-6alkyl, C3-8cycloalkyl, C1-3perfuoroalkyl,
(iii) C1-6alkoxy, methylenedioxy, C1-3perfuoroalkoxy, C1-6alkylthio,
(iv) amino, C1-6alkylamino, di-C1-6alkylamino,
(v) phenyl, phenoxy, phenylthio, halophenylthio, benzyl, benzyloxy,
(vi) hydroxycarbonyl,C1-6alkoxycarbonyl,
(vii) aminocarbonyl, C1-6alkylaminocarbonyl, di-C1-6alkylaminocarbonyl, di-C1-6alkylaminocarbonylC1-6oxy, C1-3perfluoroalkylaminocarbonyl,
(viii) C1-6acyl, C1-6acyloxy, C1-6acyloxyC1-6alkyl, C1-6acylamino, and
(ix) an aromatic heterocyclyl consisting of monocyclic radicals, wherein said radicals contain 5-6 ring atoms, wherein said radicals contain a total of from 1-4 ring heteroatoms independently selected from oxygen, nitrogen and sulfur, and where each of the said heterocyclyl groups is optionally substituted by one or more groups independently selected from halogen, C1-4alkyl, C1-4alkoxy, C1-3perfuoroalkyl and C1-3perfuoroalkoxy;
Y represents a direct or oxy link, xe2x80x94C1-6alkylene-, -oxyC1-6alkylene- or a heterocyclyl consisting of monocyclic radicals, wherein said radicals contain 5 ring atoms, and wherein said radicals contain a total of from 1-4 ring heteroatoms independently selected from oxygen, nitrogen and sulfur and wherein the ring may be independently saturated, partially unsaturated, or aromatic;
R2 represents phenyl, C3-8cycloalkyl, or a heterocyclyl consisting of monocyclic radicals, wherein said radicals contain a total of from 5-6 ring atoms, wherein said radicals contain a total of from 1-4 ring heteroatoms independently selected from oxygen, nitrogen and sulfur, wherein the ring may be independently saturated, partially unsaturated, or aromatic, and where each R2 is optionally substituted by one or more groups independently selected from halogen, C1-4alkyl, C1-4alkoxy, C3-8cycloalkyl, C1-3perfuoroalkyl, C1-3perfuoroalkoxy, hydroxycarbonyl, C1-6alkoxycarbonyl, cyano, nitro, C1-4alkylaminosulfonyl;
R3 represents hydrogen or one or more groups independently selected from halogen, C1-4alkyl, C1-4alkoxy, C1-3 perfluoroalkyl or C1-3 perfluoroalkoxy;
or a physiologically acceptable salt, solvate or derivative thereof.
Suitable physiologically acceptable salts of the compounds of general formula (I) include acid addition salts formed with pharmaceutically acceptable organic and inorganic acids for example, citrates, hydrochlorides, hydrobromides, or sulphates. Particularly preferred salts are citrates or hydrochloride salts.
The solvates may, for example, be hydrates.
References hereinafter to a compound according to the invention include both compounds of formula (I) and their physiologically acceptable salts together with physiologically acceptable solvates.
Referring to the general formula (I), alkyl, alkylene and alkoxy include both straight and branched chain saturated hydrocarbon groups. Examples of alkyl groups include methyl and ethyl groups, examples of alkylene groups include methylene and ethylene groups, whilst examples of alkoxy groups include methoxy and ethoxy groups.
Referring to general formula (I), a halogen atom may be a fluorine, chlorine, bromine or iodine atom.
Referring to the general formula (I), reference to heterocyclyl, unless otherwise defined, means any single ring or fused ring system containing at least one ring heteroatom independently selected from O, N and S. Thus, a polycyclic fused ring system containing one or more carbocyclic fused saturated, partially unsaturated, or aromatic rings (usually benz rings) is within the definition of heterocyclyl so long as the system also contains at least one fused ring which contains at least one of the aforementioned heteroatoms. As a substituent, such heterocyclyls may be attached to the remainder of the molecules from either a carbocyclic (e.g. benz) ring or from a heterocyclic ring.
Referring to the general formula (I), reference to R1 as containing one or more rings is intended to mean any single or fused cyclic moiety or moieties attached to Z. The rings may be carbocyclic or heterocyclic, saturated or partially unsaturated, and aromatic or non-aromatic.
Reference to a polycyclic ring system or radical means that all rings in the system are fused.
Referring to the general formula (I), aryl means that the ring or substituent is carbocyclic and includes phenyl and naphthyl.
Referring to the general formula (I), acyl refers to aliphatic or cyclic hydrocarbons attached to a carbonyl group through which the substituent bonds.
Referring to the general formula (I), methylenedioxy refers to a x,x+1-methylenedioxy group, where x and x+1 are integers which represent the substitiution pattern on the ring, e.g. 3,4-methylenedioxy.
Referring to the general formula (I), C1-3perfuoroalkyl or C1-3perfuoroalkoxy includes compounds such as trifluoromethyl and trifluoromethoxy.
Suitably, the piperazine or piperidine group in formula (I) is substituted meta or para, most suitably para substituted. Preferably, A represents N.
X is suitably xe2x80x94C1-6alkylene-, optionally containing by one double bond, e.g. methylene, ethylene, propylene or but-2-enylene, oxo, sulfonyl, xe2x80x94C2-6alkyleneoxy-, e.g. ethyleneoxy or propyleneoxy, xe2x80x94C1-6 alkylenecarboxy-, e.g. methylenecarboxy or xe2x80x94C1-6alkylene(Nxe2x80x94H or Nxe2x80x94C1-6alkyl)carboxamido-, e.g. methylene(Nxe2x80x94H)carboxamido.
X is equally suitably methylene, oxo, or sulfonyl. As a preferred aspect, X is a methylene group.
Z is suitably a direct link or C1-6alkylene, e.g. methylene or ethylene. Z is most suitably a direct link.
R1 is suitably selected from the following groups
(i) hydrogen, cyano, C1-3perfuoroalkyl, e.g. trifluoromethyl,
(ii) optionally substituted phenyl, where optional substitution is effected by one or two groups independently selected from C1-6 alkyl, e.g. methyl, cyano, halogen, e.g. fluoro, C1-6alkoxy, e.g. methoxy, C1-3perfuoroalkyl, e.g. trifluoromethyl, hydroxycarbonyl, C1-4alkoxycarbonyl, e.g. methoxycarbonyl, aminocarbonyl, methylenedioxy, nitro, C1-6 acyl, e.g. acetyl, phenyl, or an optionally substituted aromatic heterocycyl consisiting of monocyclic radicals and fused polycyclic radicals, wherein said radicals contain a total of 5 ring atoms, e.g. oxadiazolyl, where optional substitution is effected by C1-4 alkyl, e.g. methyl, or C1-3perfluoroalkyl, e.g. trifluoromethyl, or
(iii) an optionally substituted aromatic heterocyclyl consisiting of monocyclic radicals and fused polycyclic radicals, wherein said radicals contain a total of from 5-10 ring atoms, e.g. indolyl, pyrrolyl, thienyl, furanyl, imidazolyl, pyrazolyl, thiazolyl, pyridyl or pyrazinyl, where optional substitution is effected by C1-4alkyl, e.g. methyl, or halogen, e.g. fluorine.
Where R1 is a substituted phenyl group, substitution is suitably in the 3-position.
When R1 is an optionally substituted aromatic heterocyclyl, R1 is preferably an optionally substituted pyrrolyl, where optional substitution is effected by a methyl group. Most preferably, the substitution pattern is 2-pyrrolyl.
R1 is more suitably selected from the following groups
(i) hydrogen,
(ii) substituted phenyl, where substitution is effected by cyano or a methyl substituted oxadiazolyl group, or
(iii) a pyrrolyl group
Xxe2x80x94Z is suitably methylene or oxo and R1 is suitably phenyl or a heterocyclyl, e.g. pyrrolyl, furanyl, C-linked imidazolyl, thienyl, pyrazolyl, thiazolyl, triazolyl, indolyl, pyridyl, N-Me-imidazolyl or pyrazinyl, where each R1 is optionally substitued by one or more groups independently selected from C1-6 alkyl, e.g. methyl, cyano, halogen, e.g. fluoro, C1-6alkoxy, e.g. methoxy, trifluoromethyl, hydroxycarbonyl and C1-4alkoxycarbonyl, e.g. methoxycarbonyl.
R1 is preferably phenyl substituted by 3-cyano.
As a most preferred substitution pattern, xe2x80x94Xxe2x80x94Zxe2x80x94R1 is suitably aminocarbonylmethyl, pyrrolylmethyl or phenylmethyl substituted by cyano or methyl-oxadiazole.
Y is suitably a direct link, a 2,5-substituted oxazolyl group, or xe2x80x94(CH2)nxe2x80x94Oxe2x80x94, where n is an integer from 0-3. More suitably, Y is a direct or oxy link. Preferably Y is a direct link.
R2 is suitably cyclohexyl, a 5-6 membered aromatic heterocyclyl, e.g. pyrrolyl or pyridyl, or a phenyl group optionally substituted by one or two groups independently selected from halogen, e.g. fluoro or chloro, C1-4 alkyl, e.g. methyl, ethyl or isopropyl, C1-4 alkoxy, e.g. methoxy, or trifluoromethyl groups, where substitution is suitably in one or two of the 2-, 3-, or 4-positions on the phenyl ring. Preferably, R2 is a phenyl group substituted by a trifluoromethyl group, most preferably in the 4-position. Equally preferably, R2 is a phenyl group substituted by an isopropyl group, most preferably in the 4-position.
Preferably, Y is a direct link and R2 is a phenyl group substituted by a trifluoromethyl or isopropyl group, most preferably in the 4-position.
R3 is suitably hydrogen, halogen, e.g. chlorine, C1-4 alkyl, e.g. methyl, C1-3 perfluoroalkyl, e.g. trifluoromethyl or C1-4 alkoxy e.g. methoxy. R3 is more suitably hydrogen, halogen, e.g. chlorine, C1-4 alkyl e.g. methyl or C1-4 alkoxy e.g. methoxy. R3 is preferably a hydrogen, methyl, methoxy or chloro group. R3 is equally preferably a hydrogen, methoxy or chloro group. Substitution is preferably in the 5 or 6 position.
Particularly preferred compounds of the invention include those in which each variable in Formula (I) is selected from the preferred groups for each variable. Even more preferable compoundsof the invention include those where each variable in Formula (I) is selected from the more preferred or most preferred groups for each variable.
A suitable sub-group of a compound of formula (I) is represented by formula (Ia) 
wherein
A is CH or N;
X is suitably C1-6alkylene, optionally containing one double bond, oxo, sulfonyl, xe2x80x94C2-6alkyleneoxy-, xe2x80x94C1-6alkylenecarboxy- or xe2x80x94C1-6alkylene(Nxe2x80x94H or Nxe2x80x94C1-6alkyl)carboxamido;
Z represents a direct link or C1-6alkylene;
R1 represents one of the following groups
(i) hydrogen, C1-3perfuoroalkyl,
(ii) optionally substituted phenyl, where optional substitution is effected by one or two groups independently selected from C1-6 alkyl, cyano, halogen, C1-6alkoxy, C1-3perfuoroalkyl, hydroxycarbonyl, C1-4alkoxycarbonyl, aminocarbonyl, C1-3perfluoroalkylaminocarbonyl, methylenedioxy, nitro, C1-6 acyl, phenyl, or an optionally substituted aromatic heterocyclyl consisiting of monocyclic radicals and fused polycyclic radicals, wherein said radicals contain a total of 5 ring atoms, where optional substitution is effected by C1-4alkyl, or C1-3perfluoroalkyl,
(iii) an optionally substituted aromatic heterocycyl consisiting of monocyclic radicals and fused polycyclic radicals, wherein said radicals contain a total of from 5-10 ring atoms, where optional substitution is effected by C1-4alkyl, or C1-3perfluoroalkyl; or
(iv) where either X is C1-6alkylene and Z is a direct link, or Z is C1-6alkylene, R1 additionally may represent a cyano group;
Y represents a direct or oxy link, a 5-membered aromatic heterocyclyl group, xe2x80x94C1-6alkylene- or -oxyC1-6alkylene-;
R2 represents phenyl, C3-8cycloalkyl, or an aromatic heterocycle containing 5-6 ring atoms and 1-4 ring heteroatoms, where each ring is optionally substituted by one or more groups independently selected from halogen, C1-4alkyl, C1-4alkoxy or C1-3perfuoroalkyl;
R3 represents hydrogen, halogen, C1-4alkyl or C1-4alkoxy;
or a physiologically acceptable salt, solvate or derivative thereof.
A further suitable sub-group of a compound of formula (I) is represented by formula (Ib) 
wherein
X is methylene, oxo or sulfonyl,
Z is selected from a direct link or NH,
provided that if X is a methylene group, Z is a direct link;
R1 is selected from the following groups:
(i) hydrogen
(ii) C1-6alkoxy, C1-6alkylthio,
(iii) C1-6alkylamino, di-C1-6alkylamino C6-10 arylC1-6alkylamino, provided that Z is not NH,
(iv) unsubstuted vinyl, C6-10aryl, C3-8cycloalkyl, C3-8cycoalkenyl,
(v) C6-10 aryloxy
(vi) heterocyclyl selected from the group consisting of 5- and 6-membered heterocyclic radicals, which may be saturated, partially saturated, or aromatic, and the fused benz derivatives thereof, wherein said radicals may contain a total of from 1 to 3 ring heteroatoms independently selected from oxygen, nitrogen and sulfur,
provided that if X is CH2, R1 is selected from groups (iv) and (vi)
wherein, when R1 contains one or more rings, said rings may each independently bear 0 to 3 substituents independently selected from halogen, hydroxy, cyano, C1-6alkyt, C1-6alkoxy, C1-6alkylaminocarbonyl, di-C1-6alkylamino, di-C1-6alkylaminocarbonyl, di-C1-6alkylaminocarbonylC1-6alkoxy, C1-6acyl, C1-3perfuoroalkoxy, C1-6acyloxy, hydroxycarbonyl and C1-6alkoxycarbonyl;
Y represents a bond, an oxazolyl group, xe2x80x94Oxe2x80x94, a xe2x80x94C1-6alkylene- or an xe2x80x94Oxe2x80x94C1-6alkylene-group;
R2 represents phenyl, C3-8cycloalkyl, or a heterocycle containing 5-6 ring atoms and 1-4 ring heteroatoms, where each ring is optionally substituted by one or more groups independently selected from halogen, C1-4alkyl, C1-4alkoxy, C3-8cycloalkyl, C1-3perfuoroalkyl, C1-3perfuoroalkoxy, C1-6alkoxycarbonyl, cyano, phenyl, phenoxy, benzyl, benzyloxy;
R3 represents hydrogen or one or two groups independently selected from halogen, C1-4alkyl or C1-4alkoxy groups; or a physiologically acceptable salt, solvate or derivative thereof.
A yet further suitable sub-group of the invention is represented by a compound of formula (Ic) 
wherein
X is methylene, oxo or sulfonyl,
R1 represents phenyl or a 5-6 membered aromatic heterocyclic group, said groups being optionally substitued by one or two groups independently selected from C1-6 alkyl, cyano, halogen, C1-6 alkoxy, trifluoromethyl, hydroxycarbonyl and C1-6alkoxycarbonyl;
R2 represents phenyl substituted by one or two groups independently selected from halogen, trifluoromethyl, C1-4alkyl or C1-4alkoxy groups;
R3 represents hydrogen or one or two groups independently selected from halogen, C1-4alkyl and C1-4alkoxy groups;
or a physiologically acceptable salt, solvate or derivative thereof.
A yet further suitable sub-group of the invention is represented by a compound of formula (Id) 
wherein
R1 represents phenyl optionally substitued by one or two groups independently selected from C1-6 alkyl, cyano, halogen, C1-6 alkoxy, trifluoromethyl, hydroxycarbonyl and C1-6alkoxycarbonyl;
R2 represents phenyl substituted by one or two groups independently selected from halogen, trifluoromethyl, C1-4alkyl and C1-4alkoxy groups;
R3 represents hydrogen or one or two groups independently selected from halogen, C1-4alkyl and C1-4alkoxy groups;
or a physiologically acceptable salt, solvate or derivative thereof.
A yet further suitable sub-group of the invention is represented.by a compound of formula (Ie) 
wherein
R1 is selected from the following groups
(i) aminocarbonyl,
(ii) phenyl, optionally substituted by C1-6alkyl, cyano, halogen, C1-6alkoxy, C1-3perfuoroalkyl, hydroxycarbonyl, C1-4alkoxycarbonyl, aminocarbonyl, methylenedioxy, nitro, C1-6acyl, phenyl, or an optionally substituted 5-membered aromatic heterocyclyl, where optional substitution is effected by C1-4alkyl or C1-3perfluoroalkyl, or
(iii) an optionally substituted aromatic heterocycyl consisiting of monocyclic radicals and fused polycyclic radicals, wherein said radicals contain a total of from 5-10 ring atoms, where optional substitution is effected by C1-4alkyl;
R2 represents phenyl, optionally substituted by one or two groups independently selected from halogen, C1-3perfluoroalkyl, C1-4alkyl and C1-4alkoxy groups;
R3 represents hydrogen, halogen, C1-4alkyl or C1-4alkoxy;
or a physiologically acceptable salt, solvate or derivative thereof.
It will be clear that references herein to a compound of formula (I) apply equally to a compound of formula (Ia)-(Ie).
Particularly preferred compounds of the invention include those in which each variable of formula (I) is selected from the suitable groups for each variable. Even more preferable compounds of the invention include those where each variable in formula (I) is selected from the preferred or more preferred groups for each variable.
Suitable compounds according to the invention include:
4xe2x80x2-Trifluoromethyl-biphenyl-2-carboxylic acid [4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;
4xe2x80x2-Isopropyl-5-methyl-biphenyl-2-carboxylic acid [4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;
4xe2x80x2-Isopropyl-6-methoxy-biphenyl-2-carboxylic acid [4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;
4xe2x80x2-Isopropyl-6-methyl-biphenyl-2-carboxylic acid [4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;
6-Methyl-4xe2x80x2-trifluoromethyl-biphenyl-2-carboxylic acid [4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;
4xe2x80x2-Isopropyl-5-methyl-biphenyl-2-carboxylic acid (4-{3-(3-methyl-[1,2,4]oxadiazol-5-yl)-benzyl]-piperazin-1-yl}-phenyl)-amide;
5-Chloro-4xe2x80x2-isopropyl-biphenyl-2-carboxylic acid [4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;
6-Methoxy-4xe2x80x2-trifluoromethyl-biphenyl-2-carboxylic acid [4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;
5-Methyl-4xe2x80x2-trifluoromethyl-biphenyl-2-carboxylic acid [4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;
5-Chloro-4xe2x80x2-trifluoromethyl-biphenyl-2-carboxylic acid [4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;
Biphenyl-2-carboxylic acid (4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;
5-Methoxy-biphenyl-2-carboxylic acid [4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;
4-Chloro-4xe2x80x2-trifluoromethyl-biphenyl-2-carboxylic acid [4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyt]-amide;
N-[4-[4-(3-Cyano-benzyl)-piperazin-1-yl]-phenyl]-2-phenoxy-benzamide;
N-[4-[4-(3-Cyano-benzyl)-piperazin-1-yl]-phenyl]-2-(5-phenyl-oxazol-2-yl)-benzamide;
4xe2x80x2-Isopropyl-biphenyl-2-carboxylic acid [4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;
5-Methoxy-4xe2x80x2-trifluoromethyl-biphenyl-2-carbbxylic acid [4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;
4-Methyl-4xe2x80x2-trifluoromethyl-biphenyl-2-carboxylic acid [4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;
4-Methoxy-4xe2x80x2-trifluoromethyl-biphenyl-2-carboxylic acid [4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;
4xe2x80x2-Ethyl-biphenyl-2-carboxylic acid [4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;
4xe2x80x2-Methoxy-biphenyl-2-carboxylic acid [4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;
3xe2x80x2-Trifluoromethyl-biphenyl-2-carboxylic acid [4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;
4xe2x80x2-Fluoro-biphenyl-2-carboxylic acid [4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;
3xe2x80x2,4xe2x80x2-Dimethyl-biphenyl-2-carboxylic acid [4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;
2xe2x80x2,4xe2x80x2-Dimethyl-biphenyl-2-carboxylic acid [4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;
3xe2x80x2,4xe2x80x2-Dimethoxy-biphenyl-2-carboxylic acid [4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;
N-[4-[4-(3-Cyano-benzyl)-piperazin-1-yl]-phenyl]-2-(4-trifluoromethyl-benzyloxy)-benzamide;
N-[4-[4-(3-Cyano-benzyl)-piperazin-1-yl]-phenyl]-3-methoxy-2-(4-trifluoromethyl-benzyloxy)-benzamide;
N-[4-[4-(3-Cyano-benzyl)-piperazin-1-yl]-phenyl]-2-(4-fluoro-benzyloxy)-3-methoxy-benzamide;
N-[4-[4-(3-Cyano-benzyl)-piperazin-1-yl]-phenyl]-3-methoxy-2-phenethyloxy-benzamide;
N-[4-[4-(3-Cyano-benzyl)-piperazin-1-yl]-phenyl]-2-(2-cyclohexyl-ethoxy)-3-methoxy-benzamide;
N-[4-[4-(3-Cyano-benzyl)-piperazin-1-yl]-phenyl]-2-(2-cyclohexyl-ethoxy)-benzamide;
N-[4-[4-(3-Cyano-benzyl)-piperazin-1-yl]-phenyl]-3-methoxy-2-(3-phenyl-propoxy)-benzamide
N-4-[4-(3-Cyano-benzyl)-piperazin-1-yl]-phenyl]-2-(4-fluoro-benzyloxy)-benzamide;
4xe2x80x2-Trifluoromethyl-biphenyl-2-carboxylic acid [3-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;
4xe2x80x2-Trifluoromethyl-biphenyl-2-carboxylic acid [4-(4-carbamoylmethyl-piperazin-1-yl)-phenyl]-amide;
4xe2x80x2-Isopropyl-6-methoxy-biphenyl-2-carboxylic acid [4-(4-carbamoylmethyl-piperazin-1-yl)-phenyl]-amide;
4xe2x80x2-Isopropyl-6-methyl-biphenyl-2-carboxylic acid [4-(4-carbamoylmethyl-piperazin-1-yl)-phenyl]-amide;
6-Methyl-4xe2x80x2-trifluoromethyl-biphenyl-2-carboxylic acid [4-(4-carbamoylmethyl-piperazin-1-yl)-phenyl]-amide
4xe2x80x2-Trifluoromethyl-biphenyl-2-carboxylic acid [4-(4-cyanomethyl-piperazin-1-yl]-phenyl]-amide;
4xe2x80x2-Trifluoromethyl-biphenyl-2-carboxylic acid [4-(4-ethoxycarbonylmethyl-piperazin-1-yl)-phenyl]-amide;
4xe2x80x2-Trifluoromethyl-biphenyl-2-carboxylic acid [4-(4-(2-ethoxy-ethyl)-piperazin-1-yl]-phenyl]-amide;
4xe2x80x2-Trifluoromethyl-biphenyl-2-carboxylic acid [4-(4-(3-hydroxy-propyl)-piperazin-1-yl]-phenyl]-amide;
4xe2x80x2-Trifluoromethyl-biphenyl-2-carboxylic acid [4-(4-(4,4,4-trifluoro-butyl)-piperazin-1-yl]-phenyl]-amide;
4xe2x80x2-Trifluoromethyl-biphenyl-2-carboxylic acid [4-(4-(3-methyl-but-2-enyl)-piperazin-1-yl]-phenyl]-amide;
4xe2x80x2-Trifluoromethyl-biphenyl-2-carboxylic acid [4-(4-(3-cyano-4-fluoro-benzyl)-piperazin-1-yl)-phenyl]-amide;
4xe2x80x2-Trifluoromethyl-biphenyl-2-carboxylic acid [4-(4-(3,4-methylenedioxy-benzyl)-piperazin-1-yl)-phenyl]-amide;
4xe2x80x2-Trifluoromethyl-biphenyl-2-carboxylic acid [4-(4-(3-nitro-benzyl)-piperazin-1-yl)-phenyl]-amide;
4xe2x80x2-Trifluoromethyl-biphenyl-2-carboxylic acid {4-[4-(3-carbamoyl-benzyl)-piperazin-1-yl]-phenyl}-amide;
4xe2x80x2-Trifluoromethyl-biphenyl-2-carboxylic acid [4-[4-(3-methoxy-benzyl)-piperazin-1-yl]-phenyl]-amide;
4xe2x80x2-Trifluoromethyl-biphenyl-2-carboxylic acid [4-[4-(4-fluoro-benzyl)-piperazin-1-yl]-phenyl]-amide;
4xe2x80x2-Trifluoromethyl-biphenyl-2-carboxylic acid [4-[4-(3-fluoro-benzyl)-piperazin-1-yl]-phenyl]-amide;
4xe2x80x2-Trifluoromethyl-biphenyl-2-carboxylic acid [4-(4-benzyl)-piperazin-1-yl]-phenyl]-amide;
4xe2x80x2-Trifluoromethyl-biphenyl-2-carboxylic acid [4-[4-(3-carbomethoxy-benzyl)-piperazin-1-yl]-phenyl]-amide;
4xe2x80x2-Trifluoromethyl-biphenyl-2-carboxylic acid [4-(4-pyridin-4-ylmethyl-piperazin-1 -yl)-phenyl]-amide;
4xe2x80x2-Trifluoromethyl-biphenyl-2-carboxylic acid [4-(4-pyridin-2-ylmethyl-piperazin-1-yl)-phenyl]-amide;
4xe2x80x2-Trifluoromethyl-biphenyl-2-carboxylic acid [4-(4-pyrazin-2-ylmethyl-piperazin-1-yl)-phenyl]-amide;
4xe2x80x2-Trifluoromethyl-biphenyl-2-carboxylic acid [4-(4-thiazol-2-ylmethyl-piperazin-1-yl)-phenyl]-amide;
4xe2x80x2-Trifluoromethyl-biphenyl-2-carboxylic acid [4-[4-(1-methyl-1H-imidazol-2-ylmethyl)-piperazin-1-yl)-phenyl]-amide;
4xe2x80x2-Isopropyl-6-methyl-biphenyl-2-carboxylic acid (4-(4-(3-(3-methyl-[1,2,4]oxadiazol-5-yl)-benzyl)-piperazine-1-yl)-phenyl)-amide;
4xe2x80x2-Trifluoromethyl-biphenyl-2-carboxylic acid [4-(4-(1H-pyrrol-2-ylmethyl)-piperazin-1-yl)-phenyl]-amide;
4xe2x80x2-Isopropyl-5-methyl-biphenyl-2-carboxylic acid [4-(4-(1H-pyrrol-2-ylmethyl)-piperazin-1-yl)-phenyl]-amide;
5-Methyl-4xe2x80x2-trifluoromethyl-biphenyl-2-carboxylic acid [4-(4-(1H-pyrrol-2-ylmethyl)-piperazin-1-yl)-phenyl]-amide;
4xe2x80x2-Trifluoromethyl-biphenyl-2-carboxylic acid [4-(4-propyl-piperazin-1-yl)-phenyl]-amide;
4xe2x80x2-Trifluoromethyl-biphenyl-2-carboxylic acid [4-(4-(3-acetyl-benzyl)-piperazin-1-yl)-phenyl]-amide;
4xe2x80x2-Trifluoromethyl-biphenyl-2-carboxylic acid [4-(4-furan-2-ylmethyl-piperazin-1-yl)-phenyl]-amide;
4xe2x80x2-Isopropyl-6-methoxy-biphenyl-2-carboxylic acid [4-(4-(1H-pyrrol-2-ylmethyl)-piperazin-1-yl)-phenyl]-amide;
4xe2x80x2-Trifluoromethyl-biphenyl-2-carboxylic acid [4-(4-(1-methy)-1H-pyrrol-2-ylmethyl)-piperazin-1-yl)-phenyl]-amide;
4xe2x80x2-Trifluoromethyl-biphenyl-2-carboxytic acid [4-(4-thiophen-2-ylmethyl-piperazin-1-yl)-phenyl]-amide;
4xe2x80x2-Trifluoromethyl-biphenyl-2-carboxylic acid {4-[4-(1H-pyrazole-3-ylmethyl)-piperazine-1-yl]-phenyl}amide;
4xe2x80x2-Trifluoromethyl-biphenyl-2-carboxylic acid [4-(4-thiophen-3-ylmethyl-piperazin-1-yl)-phenyl]-amide;
4xe2x80x2-Trifluoromethyl-biphenyl-2-carboxylic acid {4-[4-(5-fluoro-1H-indol-3-ylmethyl)-piperazin-1-yl]-pheny}-amide;
4xe2x80x2-Isopropyl-6-methoxy-biphenyl-2-carboxylic acid (4-(4-(3-(3-methyl-[1,2,4]oxadiazol-5-yl)-benzyl)-piperazine-1-yl)-phenyl)-amide;
4xe2x80x2-Trifluoromethyl-biphenyl-2-carboxylic acid (4-{4-[3-(5-trifluoromethyl-[1,2,4]oxadiazol-3-yl)-benzyl]-piperazin-1-yl}-phenyl)-amide; (4-{4-[(4xe2x80x2-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-piperazin-1-yl]-acetic acid;
4xe2x80x2-trifluoromethyl-biphenyl-2-carboxylic acid [4-(4-{[(biphenyl-3-ylmethyl)-carbamoyl]-methyl}-piperazin-1-yl)-phenyl]-amide;
3-(4-{4-[(4xe2x80x2-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-piperazin-1 -ylmethyl)-benzoic acid;
4xe2x80x2-Trifluoromethyl-biphenyl-2-carboxylic acid (4-{4-[3-(2,2,2-trifluoro-ethylcarbamoyl)-benzyl]-piperazin-1-yl}-phenyl)-amide;
4xe2x80x2-Trifluoromethyl-biphenyl-2-carboxylic acid [4-[4-(3-cyano-benzoyl)-piperazin-1-yl]-phenyl]-amide;
4xe2x80x2-Trifluoromethyl-biphenyl-2-carboxylic acid [4-(4-acetyl-piperazin-1-yl)-phenyl]-amide;
4xe2x80x2-Trifluoromethyl-biphenyl-2-carboxylic acid [4-[4-(3-cyano-benzenesulfonyl)-piperazin-1-yl]-phenyl]-amide;
4xe2x80x2-Trifluoromethyl-biphenyl-2-carboxylic acid [4-(4-methanesulfonyl-piperazin-1-yl)-phenyl]-amide;
4xe2x80x2-Trifluoromethyl-biphenyl-2-carboxylic acid [4-[1-(3-cyano-benzyl)-piperidin-4-yl]-phenyl]-amide;
N-{4-[4-(3-Cyano-benzyl)-piperazin-1-yl]-phenyl}-2-pyrrol-1-yl-benzamide;
N-{4-[4-(3-Cyano-benzyl)-piperazin-1-yl]-phenyl}-2-pyridin-2-yl-benzamide;
or a physiologically acceptable salt, solvate or derivative thereof.
Preferred compounds of the invention include:
4xe2x80x2-Trifluoromethyl-biphenyl-2-carboxylic acid [4-[4-(3-cyano-benzyl)-piperazin-1 -yl]-phenyl]-amide;
4xe2x80x2-Isopropyl-5-methyl-biphenyl-2-carboxylic acid [4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;
4xe2x80x2-Isopropyl-6-methoxy-biphenyl-2-carboxylic acid [4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;
4xe2x80x2-Isopropyl-6-methyl-biphenyl-2-carboxylic acid [4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;
6-Methyl-4xe2x80x2-trifluoromethyl-biphenyl-2-carboxylic acid [4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;
4xe2x80x2-Isopropyl-5-methyl-biphenyl-2-carboxylic acid (4-{3-(3-methyl-[1,2,4]oxadiazol-5-yl)-benzyl]-piperazin-1-yl}-phenyl)-amide;
4xe2x80x2-Trifluoromethyl-biphenyl-2-carboxylic acid [4-(4-carbamoylmethyl-piperazin-1-yl)-phenyl]-amide;
4xe2x80x2-Isopropyl-6-methoxy-biphenyl-2-carboxylic acid [4-(4-carbamoylmethyl-piperazin-1-yl)-phenyl]-amide;
4xe2x80x2-Isopropyl-6-methyl-biphenyl-2-carboxylic acid [4-(4-carbamoylmethyl-piperazin-1-yl)-phenyl]-amide;
4xe2x80x2-Isopropyl-6-methyl-biphenyl-2-carboxylic acid (4-(4-(3-(3-methyl-[1,2,4]oxadiazol-5-yl)-benzyl)-piperazine-1-yl)-phenyl)-amide;
4xe2x80x2-Trifluoromethyl-biphenyl-2-carboxylic acid [4-(4-(1H-pyrrol-2-ylmethyl)-piperazin-1-yl)-phenyl]-amide;
4xe2x80x2-Isopropyl-5-methyl-biphenyl-2-carboxylic acid [4-(4-(1H-pyrrol-2-ylmethyl)-piperazin-1-yl)-phenyl]-amide;
5-Methyl-4xe2x80x2-trifluoromethyl-biphenyl-2-carboxylic acid [4-(4-(1H-pyrrol-2-ylmethyl)-piperazin-1-yl)-phenyl]-amide;
or a physiologically acceptable salt, solvate or derivative thereof.
The term xe2x80x9cphysiologically functional derivativexe2x80x9d as used herein refers to any physiologically acceptable derivative of a compound of the present invention, for example, an ester, which upon administration to a mammal, such as a human, is capable of providing (directly or indirectly) such a compound or an active metabolite thereof. Such derivatives are clear to those skilled in the art, without undue experimentation, and with reference to the teaching of Burgerxe2x80x2s Medicinal Chemistry And Drug Discovery, 5th Edition, Vol 1: Principles And Practice, which is incorporated herein by reference.
The compounds of the invention are inhibitors of hepatic production of apoB-100 and are thus of use in the treatment of conditions resulting from elevated circulating levels of apoB-100.
The ability of the compounds of the invention to inhibit the production of apoB-100 by human hepatocytes in vitro is determined using primary human hepatocytes as a model system. The specificity of the compounds of the invention is established by comparing the effects on apoB-100, apoprotein A-1, and fibrinogen production. A specificity of at least 100 is preferred.
The in vivo profile of the compounds was determined by acute oral administration of the compounds of the invention to DBN/2 mice and Wistar rats with measurement of apoB-100 plasmatic levels as percentage of control values. Active compounds are further evaluated in Wistar rats by repeated oral administration (once a day) with measurement of total cholesterol, low density lipoprotein-cholesterol, triglycerides, apoB-100 and apoA-1 plasmatic levels as a percentage of control values.
The compounds of the invention are potent and specific inhibitors of hepatic production of apoB-100, which furthermore exhibit good oral bioavailability and duration of action.
Compounds of the invention are of use in the treatment of atherosclerosis, pancreatitis, non-insulin dependent diabetes mellitus (NIDDM), and coronary heart diseases.
Compounds of the invention are also useful in lowering serum lipid levels, cholesterol and/or triglycerides, and are of use in the treatment of hyperlipemia, hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia and/or hypertriglyceridemia.
The invention therefore provides a compound of formula (I) or a physiologically acceptable salt, solvate or derivative thereof for use in therapy, in particular in human medicine.
There is also provided as a further aspect of the invention the use of a compound of formula (I) or a physiologically acceptable salt, solvate or derivative thereof in the preparation of a medicament for use in the treatment of conditions resulting from elevated circulating levels of apoB-100.
In an alternative or further aspect there is provided a method for the treatment of a mammal, including man, in particular in the treatment of conditions resulting from elevated circulating levels of apoB-100, comprising administration of an effective amount of a compound of formula (I) or a physiologically acceptable salt, solvate or derivative thereof.
It will be appreciated that reference to treatment is intended to include prophylaxis as well as the alleviation of established symptoms. Compounds of formula (I) may be administered as the raw chemical but the active ingredient is preferably presented as a pharmaceutical formulation.
Accordingly, the invention also provides a pharmaceutical composition which comprises at least one compound of formula (I) or a physiologically acceptable salt, solvate or derivative thereof and formulated for administration by any convenient route. Such compositions are preferably in a form adapted for use in medicine, in particular human medicine, and can conveniently be formulated in a conventional manner using one or more pharmaceutically acceptable carriers or excipients.
Thus compounds of formula (i) may be formulated for oral, buccal, parenteral, transdermal, topical (including ophthalmic and nasal), depot or rectal administration or in a form suitable for administration by inhalation or insufflation (either through the mouth or nose).
For oral administration, the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium starch glycollate); or wetting agents (e.g. sodium lauryl sulphate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifylng agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g. methyl or propyl p-hydroxybenzoates or sorbic acid). The preparations may also contain buffer salts, flavouring, colouring and sweetening agents as appropriate.
Preparations for oral administration may be suitably formulated to give controlled release of the active compound.
For buccal administration the composition may take the form of tablets or lozenges formulated in conventional manner.
For transdermal administration the compounds according to the invention may be formulated as creams, gels, ointments or lotions or as a transdermal patch. Such compositions may for example be formulated with an aqueous or oily base with the addition of suitable thickening, gelling, emulsifylng, stabilising, dispersing, suspending, and/or colouring agents.
The compounds of the invention may be formulated for parenteral administration by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosageform e.g. in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
The compounds of the invention may be formulated for topical administration in the form of ointments, creams, gels, lotions, pessaries, aerosols or drops (e.g. eye, ear or nose drops). Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Ointments for administration to the eye may be manufactured in a sterile manner using sterilised components.
Lotions, may be formulated with an aqueous or oily base and will in general also contain one or more emulsifylng agents, stabilising agents, dispersing agents, suspending agents, thickening agents, or colouring agents. Drops may be formulated with an aqueous or non aqueous base also comprising one or more dispersing agents, stabilising agents, solubilising agents or suspending agents. They may also contain a preservative.
The compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.
The compounds of the invention may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds of the invention may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
For intranasal administration, the compounds of the invention may be formulated as solutions for administration via a suitable metered or unit dose device or alternatively as a powder mix with a suitable carrier for administration using a suitable delivery device.
The compositions may contain from 0.1% upwards, e.g. 0.1-99% of the active material, depending on the method of administration. A proposed dose of the compounds of the invention is 0.25 mg/kg to about 125 mg/kg bodyweight per day e.g. 20 mg/kg to 100 mg/kg per day. It will be appreciated that it may be necessary to make routine variations to the dosage, depending on the age and condition of the patient and the precise dosage will be ultimately at the discretion of the attendant physician or veterinarian. The dosage will also depend on the route of administration and the particular compound selected.
The compounds of formula (I) may, if desired, be administered with one or more therapeutic agents and formulated for administration by any convenient route in a conventional manner. Appropriate doses will be readily appreciated by those skilled in the art. For example, the compounds of formula (I) may be administered in combination with an HMG CoA reductase inhibitor.
A compound of formula (I), or a physiologically acceptable salt, solvate or derivative thereof, may be prepared by the general methods outlined hereafter. In the following description, the groups X, Y, Z, R1, R2 and R3 are as previously defined for compounds of formula (I), unless specified otherwise.
According to a general process (A), a compound of formula (I) may be prepared by reacting a compound of formula (II) with a compound of formula Rxe2x80x2xe2x80x94Zxe2x80x94Xxe2x80x94L 
where L represents a suitable halide leaving group, e.g. chloride, under standard displacement conditions, or where X is an oxo group, L may additonally represent a hydroxy group, the reaction being effected under standard acid and amine coupling conditions.
A compound of formula (II) may be prepared by reaction of a compound of formula (III) with a compound of formula (IV) 
where L is defined above and P is a suitable amine protecting group, e.g. tert-butoxycarbonyl (Boc), under standard coupling conditions for an acid and amine coupling, followed by deprotection of the protecting group under suitable conditions, e.g. acidic removal of a Boc group.
A compound of formula (IV), where A represents N, may be prepared by the two step reaction of a compound of formula (V) 
comprising incorporation of the protecting group P using standard methodology followed by reduction of the nitro group, e.g. under hydrogenation conditions.
A compound of formula (IV), where A represents CH, may be prepared from a compound of formula (VI) 
by reaction with a suitable a compound of formula H2Nxe2x80x94Pxe2x80x2 where Pxe2x80x2 is a suitable protecting group which is labile under hydrogenation conditions, such as a benzyl group, using a suitable coupling agent or agents such as tris(dibenzylidene acetone)dipalladium, 2,2xe2x80x2-bis(diphenylphosphino)-1,1xe2x80x2-binaphthyl (binap) and sodium tert-butoxide in a suitable solvent such as toluene, followed by removal of the protecting group and reduction of the double bond under hydrogenation conditions.
According to a second method (B), compounds of formula (I) may be prepared by reaction of compounds of formula (III) and compounds of formula (VII) 
where L is defined above, under standard coupling conditions.
Compounds of formula (VII) may be prepared by reaction of a compound of formula (V) With a compound of formula R1xe2x80x94Zxe2x80x94Xxe2x80x94L, where L is defined above, followed by reduction of the nitro group under hydrogenation or reductive tin chloride conditions.
According to a third process (C), a compound of formula (I) where Y is xe2x80x94Oxe2x80x94C1-4alkylene- may be prepared by reaction of a compound of formula (VIII) with a compound of formula R2xe2x80x94C1-4alkylene-L, where L is defined above, 
Compounds of formula (VIII) may be prepared according to the process outlined in process B.
According to a fourth general process (D), a compound of formula (I), where at least part of X represents an alkylene link to the piperidine or piperazine-group, may be prepared by reacting a compound of formula (II) with a compound of formula (IX) 
where Xxe2x80x2 represents X minus a methylene group, under standard reductive amination conditions, e.g. using sodium triacetoxyborohydride in a solvent such as dichloroethane.
According to a fifth process (E), a compound of formula (I) may be prepared from a different compound of formula (I), using standard techniques well known in the art. For example, compounds of formula (I) where R1 comprises a group containing an amide group may be prepared from the compound of formula (I) where the corresponding position comprises a carboxylic acid group, which in turn may be prepared from the compound of formula (I) where the corresponding position comprises a carboxylic ester group. Well known methods in the art may be employed to facilitate the transformation of an ester to an acid and then to an amide.
A compound of formula (III), where Y is a direct link, R2 is a phenyl or an aromatic heterocyclyl and L is a hydroxy group, may be prepared firstly by coupling a boronic acid with a suitable leaving group, represented by a compound of formula (X) and a compound of formula (XI) 
where R2xe2x80x2 represents phenyl or an aromatic heterocyclyl, PG represents a protected carboxylic acid and A and D represent either the boronic acid or the suitable leaving group, such as triflate or bromide, followed by deprotection of the protecting group under standard conditions, such as base removal of an ester group. Where L represents a halide leaving group, the carboxylic acid product can be treated with a suitable reagent, such as thionyl chloride, to give the corresponding chloride leaving group.
Where R1 is a phenyl, substituted by an aromatic he terocyclyl, the aromatic heterocyclyl may be introduced by any well known methods in the art. For instance, where the substituent is a methyl substituted oxadiazole, this may be formed by treatment of a suitable benzamide derivative with a suitable reagent, such as dimethylacetamide dimethylacetal at elevated temperature, followed by cyclisation of the intermediate compound with hydoxylamine.
The various general methods described above may be useful for the introduction of the desired groups at any stage in the stepwise formation of the required compound, and it will be appreciated that these general methods can be combined in different ways in such multi-stage processes. The sequence of the reactions in multi-stage processes should of course be chosen so that the reaction conditions used do not affect groups in the molecule which are desired in the final product.
Compounds of formula R1xe2x80x94Zxe2x80x94Xxe2x80x94L, (III), (V) and (VI), (IX), (X) and (XI) are known or may be prepared by standard methods well known in the art and/or herein described.
Physiologically acceptable salts may also be prepared from other salts, including other physiologically acceptable salts, of the compound of formula (I) using conventional methods.
The compounds of formula (I) may readily be isolated in association with solvent molecules by crystallisatioq from or evaporation of an appropriate solvent to give the corresponding solvates.
When a specific enantiomer of a compound of general formula (I) is required, this may be obtained for example by resolution of a corresponding enantiomeric mixture of a compound of formula (I) using conventional methods.
Thus, in one example an appropriate optically active acid may be used to form salts with the enantiomeric mixture of a compound of general formula (I). The resulting mixture of isomeric salts may be separated, for example, by fractional crystallisation into the diastereoisomeric salts from which the required enantiomer of a compound of general formula (I) may be isolated by conversion into the required free base.
Alternatively, enantiomers of a compound of general forrmula (I) may be synthesised from the appropriate optically active intermediates using any of the general processes described herein.
The invention is further illustrated by the following intermediates and examples. All temperatures are in degrees centigrade.
Abbreviations:
MS-LCMS mass spectrography, HOBt-1-Hydroxybenzotriazole, AcOEt-Ethyl acetate, EDCl-1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, BINAP-2,2xe2x80x2-bis(diphenylphosphino)-1,1xe2x80x2-binaphthyl, THF-Tetrahydrofuran, MeOH-Methanol, EtOH-Ethanol, Et3N-Triethylamine